Positron Emission

Tomography (PET):

Synthesis of short-lived

11C and 18F radionuclide tracers

Sarah Decato2/16/2012

Ostrovsky, G. http://medgadget.com/2011/06/siemens-biograph-mmr-mrpet-scanner-gets-eu-green-light.html (accessed 1/29/2011).

Background Outline

• Imaging Modalities

• PET physics

• PET radionuclides

• Tracer parameters

Ostrovsky, G. http://medgadget.com/2011/06/siemens-biograph-mmr-mrpet-scanner-gets-eu-green-light.html (accessed 1/29/2011).

2

Growth of PET

0

100

200

300

400

500

600

700

Year

Pu

bli

cati

on

Cou

nt

3

Jaroff, L. http://www.time.com/time/magazine/article/0,9171,998685,00.html (accessed 2/10/12).

Imaging Modalities• Anatomical Imaging: Visualization of body

structure; can only diagnose structural abnormalities.o X-rayo Computed tomography (CT)o Magnetic resonance imaging (MRI)

• Molecular Imaging: Target unique tissues or cell types with specific probes with the aim to monitor and diagnose diseases, study biological processes, evaluate drug efficacy. o Positron emission tomography (PET)o Single-photon emission computed tomography (SPECT)

4Ametamey, S. M., Chem. Rev. 2008, 108, 1501-1516.

Imaging Modalities: PET

Advantages

• No imaging “handle” necessary

• Mass of probe is subtoxicological

• Beneficial multimodality capability (PET/CT, PET/MRI)

Imaging modality

Form of energy

Spatial resolution (mm)

Acquisition time

(s)

Probe mass (ng)

Tissue depth (mm)

Cost

PET Annihilation photons 1-4 1-300 1-100 >300 High

Ultrasound

Sound waves 0.05-0.5 0.1-100 103-106 1-200 Low

5Levin, C. S., European Journal of Nuclear Medicine and Molecular Imaging 2005, 32, S325-S345., Diagnostic Imaging

http://www.diagnosticimaging.com/display/article/113619/1412709?pageNumber=3 (accessed 2/3/2012).

CT Overlay

PET

PET Physics: Positron Decay

Radionuclide Decay product11C 11B18F 18O13N 13C15O 15N

β+ ν

Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47, 8998-9033.

positron

neutrino

Spontaneous

6

PET Physics: Coincidence Event

γ γ

ν

β-β+

annihilation

photon detection

photon detection

decay path

Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47, 8998-9033.

7

PET Radionuclides: Selection

Nuclide Half-life (min.)

Max. energy (MeV)

Decay Mode (%)a

Max. Specific Activity

(GBq/µmol)

18F 110 0.64 97 6.3 x 104

11C 20.3 0.97 99 3.4 x 105

13N 10 1.20 100 7.0 x 105

15O 2 1.74 100 3.4 x 106

76Br 972 4.00 57 7.2 x 103

124I 60,192 2.14 25 1.5 x 103

68Ga 68.1 1.90 89 1.02 x 105

64Cu 762 0.655 19b 9.13 x 103

aRemaining decay percentage is from electron capturebRemaining decay percentage is from 41% electron capture and 40% β- decay

8Ametamey, S. M., Chem. Rev. 2008, 108, 1501-1516.

PET Physics: Cyclotron

• A charged particle moves through a magnetic field• The beam travels in a circle and the particle accelerates

through the electric field region (gap)• Nuclear reaction occurs as the beam hits the target

Ametamey, S. M., Chem. Rev. 2008, 108, 4036-4036., Encyclopedia Britannica http://www.britannica.com/EBchecked/media/59676/Plan-view-of-a-classical-cyclotron-Subatomic-particles-introduced-into

(accessed 2/2/2012).

9

PET Radionuclides: Synthesis

Target Nuclear Reaction

Product

11C N2 (+O2) 14N (p,α) 11C 11CO2

N2 (+H2) 11CH4

18F Ne (+19F2) 20Ne (d,α) 18F 18F-19F

H218O 18O (p,n) 18F 18F-

aX(d,n)bY target nucleus

product nucleusaccelerated

particle emittedparticle

Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47, 8998-9033.

10

UW - Madison

UW – Madison Cyclotron/PET Research Center http://www.medsch.wisc.edu/cycl/default.html (accessed 2/2/2012).

11

Tracer Parameters• Time

o Half-lifeo Preparation time < 3 half-liveso Transport

• Scale (µL – nL)• Modifications to biological

properties (18F)• Label position

o 2-fluoro-2-deoxy-glucose (FDG)

• Radiochemical yield (%RCY)• Specific activity (GBq/µmol)

o 74GBq/µmol

OHO

HO 18F

OH

OH

18FDG

12Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47, 8998-9033., Zheng, Q.-H., et al., Biomed. Chromatogr. 2005,

19, 671-676.

Synthesis Outline• 11C

o Radiolabeling precursors

o 11CO2

o 11CO o Methylation

• 18Fo Radiolabeling

precursorso Electrophilic

fluorinationo Nucleophilic

fluorinationo Iodonium saltso Late stage fluorination

Yale School of Medicine http://petcenter.yale.edu/index.aspx (accessed 2/2/2012).

13

Radiolabeling Precursors: 11C

14N (p,α) 11C

11CO2

11CH3I

11CH3OTf

11CO

R11CO2MgX

11CH4

N2 (+H2)

1) LiAlH4 2) HI

“wet method”

“dry method”

N2 (+O2)

I2, 720°C

Mo, 820°C

RMgX

AgOTf

EOB

14Pretze, M., et al., Molecules 2011, 16, 1129-1165., Scott, P. J. H., Angew. Chem. Int. Ed. 2009, 48, 6001-6004., Ametamey, S.

M., Chem. Rev. 2008, 108, 1501-1516., Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47, 8998-9033.

CO2: GrignardWAY100635

OCH3

N

NN

O

N I

Analog of 5-HT1A

receptor antagonist: p-

MMPI

R-MgX 11CO2

RCO

OMgX

1. R1R2NH, THFµw, 2-10min

2. H2SO4, H2O 20-65% RCY

RCO

N

R2

R1

MgCl 1. 11CO2

3. SOCl2, 75°C, 5min

2. HCl, THF

CClO

WAY100364

NEt3, THF 75°C, 5min2.3% RCY

OCH3

N

NN

CO

N

15Hwang, D.-R., et al., Nuc. Med. Biol. 1999, 26, 815-819., Lu, S.-Y., et al., J. Label.Compd. Radiopharm. 2003, 46,

1249-1259.

CO: Low Solubility• CO does not suffer from significant isotopic

dilution• CO is limited by :

o Low solubility in organic solventso Low reactivity at or near atmospheric pressure

16

BH3 THF + 11CO BH3.11CO + THF

I

NH2C

NH

O

Pd(OAc)2/PPh3,TEA, THF(1%H2O)

70°C, 8min 47% RCY

Audrain, H., et al., Chem. Commun. 2004, 558-559., Långström, B., et al., J. Label. Compd. Radiopharm. 2007, 50, 794-810.

I

R1

[Pd2(dba)3]/P(o-tolyl)3/DMSO125°C, 5min 37-98% RCY

300 GBq/µmol

11CO, SnR24

R1 = H, OCH3, NH2, Cl, CH3, OH, COOH, CN, NO2

C

R1

R2

O

R1 = H R2 = CH3(CH2)n n = 0 - 4

R1 = OCH3, NH2, Cl, CH3, OH

COOH, CN, NO2 R2 = CH3

CO: Palladium-mediated

Palladium-mediated

11C-carbonylation reactions

Stille

Suzuki

Y OTf

Pd(PPh3)4, KOt-Bu, THFLiBr, 150°C, 5min

14-79% RCY, 150-640 GBq/µmol

11CO, RB(OH)2

Y = CH or N

Y CR

O

R = Me, Bu, Ph, PhCH2CH2

4-F-Ph, 4-NO2-Ph

17Långström, B., et al., J. Label. Compd. Radiopharm. 2007, 50, 794-810., Rahman, O., et al., Eur. J. Org. Chem. 2004, 2004, 2674-2678.,

Karimi, F., et al., Eur. J. Org. Chem. 2005, 2005, 2374-2378., Hostetler, E. D., et al., Nuc. Med. Biol. 2002, 29, 845-848., Rahman, O., et al., Eur. J. Org. Chem. 2004, 2004, 474-478.

Simple Methylation

• O, S, N alkylation • Captive solvent method or loops allow for increased reactivity

with milder conditions• General method under mild conditions

[11C]raclopride

[11C]flumazanil

Wilson, A. A., et al., Nuc. Med. Biol. 2000, 27, 529-532., Cleij, M. C., et al., J. Label. Compd. Radiopharm. 2007, 50, 19-24.

Cl

Cl

OH

OH

O

NH

N Cl

Cl

O

OH

O

NH

N

H311C

11CH3I

captive solvent methodr.t., 48GBq/µmol

NH

N

O

F

N O

O

N

N

O

F

N O

O11CH3I, DMF/KOH

captive solvent methodr.t., 525 GBq/µmol 11CH3

18

11CH3I from cyclotron

HPLC

Trap

Loop

Detector

Methylation: Stille Cross-coupling

Hosoya, T., et al., Org. Biomol. Chem. 2006, 4, 410-415., Samuelsson, L., et al., J. Label. Compd. Radiopharm. 2003, 46, 263-272., Hamill, T. G., et al., Synapse 2005, 56, 205-216.

NH

O

ON

O

OH

HO F

(H3C)3Sn 11CH3I

[Pd2(dba)3]/P(o-tolyl)3/DMF130°C, 5min 30% RCY

0.8 GBq/µmol

NH

O

ON

O

OH

HO F

H311C

NC

Sn(CH3)3

N

S

11CH3I

[Pd2(dba)3]/P(o-tolyl)3/CuCl/K2CO3/DMF

22% RCY

NC

11CH3

N

S

FMAU

M-TEB ligand (mGluR5) 19

Methylation: Suzuki

Sanchez-Pernaute, R., et al., NeuroImage 2008, 42, 248-251., Hostetler, E. D., et al., J. Label. Compd. Radiopharm. 2005, 48, 629-634., Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47, 8998-9033.

NC

B(OH)2

N

S

11CH3I

[Pd(dppf)Cl2/K3PO4/DMFµw, 90s, 28.5% RCY

70.4GBq/µmol

NC

11CH3

N

S

Y RCY

o-Br 49-67%

o-NO2 57-90%

p-OH 92-95%

m-CHO 62-92%

p-COOH 69-72%

p-COOMe 80-93%

p-NHCOMe 85-96%

BR

Y

11CH3

Y

11CH3I

[Pd(dppf)Cl2/K3PO4/DMFµw, 100°C, 90s

R = (OH)2 or pinacol

Y = Br, NO2, OH, CHO, COOH, COOMe, NHCOMe

20

Methylation: Transfer Reagent

(Allyl-PdCl)2, DMF, 100°C, 20-90% RCY, 0.2-0.9 GBq/µmol

R

X

R

11CH3

R = H, p-MeO, o-NH2, m-NO2, p-CN, p-COOEt, p-OH

Sn[N(TMS)2]21. 11CH3I

2. TBAFH3

11C Sn

F

F

N(TMS)2

N(TMS)2Ar-11CH3

Pd2(dba)3

dioxane 120°C, 5min60-95% RCY

ArBr or ArI

Ar = quinoline,napthalene or benzene moiety

21Forngren, T., et al., J. Label. Compd. Radiopharm. 2004, 47, 71-78., Huiban, M., et al., Chem.

Commun. 2006., 97-99.

NSnCl

11CH3Li

THF, -78°C-r.t, 4min

NSn11CH3

11CH3I

nBuLi

11C Summary• 11CO2 is a traditional yet mainly inefficient

method to perform 11C-labeling.

• 11CO is versatile but needs to be modified or trapped to become effectively reactive.

• Direct methylation can be achieved with captive solvent methods or Pd-mediated cross-couplings with 11CH3I.

22

18O(p,n)18

F

K18F-

“18F-”

Radiolabeling Precursors: 18F

20Ne(d,α)18

F

18F–19F

CH3CO218F

19F2

AcOH AcOK

K2CO3

H2O/ACN

“K2.2.2

”

23Schirrmacher, R., et al., Mini-Reviews in Organic Chemistry, 2007, 4, 317-329., Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47,

8998-9033., Pretze, M., et al., Molecules 2011, 16, 1129-1165.

Electrophilic

Nucleophilic

Electrophilic Fluorination

BocO

SnMe3

HCOOEt

NHBoc HO

18F

HCOOH

NH2

1. 18F-19F

2. HBr42% RCY

1. CH3CO218F

2. HBr 6.4% RCY

Me3Sn

BocO

OH

NHBoc18F

HO

OH

NH2

18F-L-Tyrosine

18F-L-DOPA

24Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47, 8998-9033., Hess, E., et al., Appl. Radiat. Isot.

2002, 57, 185-191.

Nucleophilic Fluorination

OHO

HO18F

OH

OH

OAcO

AcO18F

OAc

OAc

OAcO

AcO

OAc

OAc

K18F.K2.2.2 HClOTf

MeCN 50 min>50% RCY

FDG

Y

X

Y = (o-, p-) NO2, CN, CHO, COR, COORX = NO2, (CH3)3N+

18F-

Y

18F

DMSO

SNAr most prevalent 18F labeling technique

Substitutions on heterocylic systems (pyridine) do not require activating groups (Y)

OCH3

N

NN

O

N 18F

MPPF

25Furuya, T., et al., Synthesis 2010, 2010, 1804-1821., Ehrenkaufer, R. E., et al., Journal of Nuclear Medicine 1984, 25, 333-337., Telu, S., et al., Org. Biomol. Chem. 2011, 9, 6629-6638., Hamacher, K., et al., Journal of Nuclear Medicine 1986, 27,

235-238.

Iodonium Salts

I

I

I

18F-, K2.2.2.

18F

I

X

X = Cl, OTs, OTf

DMF, 120°C70% RCY

26Wang, B., et al., J. Fluorine Chem. 2010, 131, 1113-1121., Littich, R., et al., Angew. Chem. Int. Ed. 2012, 51, 1106-

1109., Ross, T. L., et al., J. Am. Chem. Soc. 2007, 129, 8018-8025., Pretze, M., et al., Molecules 2011, 16, 1129-1165.

R

I S

Br18F-, K2.2.2.

DMF, 130°C

18F

R

SI

R = 3-OMe, 20% RCY 4-OMe, 29% RCY 2-OMe, 61% RCY

Iodonium Salts: Pd Coupling Precursor

NH

O

ON

O

OAcOAc

AcO

18F

NH

O

ON

O

OHOH

HO

18F

NH

O

ON

O

OAcOAc

AcO

Bu3Sn

Pd2(dba)3/CuIAsPh3

DMF/dioxane65°C, 20 min

1M KOH

61% RCY

18F

IBR

Y[Pd2(dba)3, Cs2CO3/ACN60°C, 5min 30-90% RCY

R = (OH)2 or pinacol

Y = H, Me, F, Cl, Br, NO2, OH, COOH, COOMe, SMe, SO2Me

Y

18F

Stille

Suzuki

27Ross, T. L., et al., J. Am. Chem. Soc. 2007, 129, 8018-8025., Schirrmacher, R., et al., Mini-Reviews in Organic Chemistry, 2007, 4,

317-329., Pretze, M., et al., Molecules 2011, 16, 1129-1165.

Late Stage Fluorination: Selectfluor

NN

Cl

2 -OTf

1. DCM/Acetone (1:1).

NN

18F

2. LiOTf, MeCN, -10°C

3. 18F-19F

total reaction time 25 min4-7 GBq Selectfluor

bis(triflate)

R2

R3O

SnR13 R2

R3O

18F1

AgOTf (2eq.)

acetone, r.t. 20min

R1 = Me, R2 = OMe, R3 = Me; 18% RCYR1 = Me, R2 = H, R3 = Me; 17% RCYR1 = Bu, R2 = H, R3 = H; 14% RCY

OSiMe3

Me

1MeCN, 5-15 min

80°C, up to 50% RCY16 GBq/µmol

O

Me

18F

28Littich, R., et al., Angew. Chem. Int. Ed. 2012, 51, 1106-1109.

1

PdN

N

N

N

N

Me

N

N

BN

NN

22 OTf

PdN

N

N

18F

NN

N

BN

NN

OTf

18F-

[18]-crown-6KHCO3, acetone

23°C, 10 min

H H

H

Me O

[Pd]

H H

H

Me O

18F

acetone, 85°C10 min, 33% RCY

Late Stage Fluorination: Ritter

Catalyst

fluorodeoxyestrone

29Lee, E., et al., Science 2011, 334, 639-642., Furuya, T., et al., J. Am. Chem. Soc. 2010, 132, 3793-3807., Littich, R., et al., Angew. Chem.

Int. Ed. 2012, 51, 1106-1109.

Pd

N

OAc

NN

SO

O

OMe

Pd

N

NN

SO

O

OMe

R

benzene/MeOH (1:1)K2CO3

23°C, 10h, >90%

R

B(OH)2

R

[Pd]

1

1

• Electrophilic fluorination results in low specific activity and low selectivity

• Nucleophilic methods are most common but limited to electron-deficient aromatic systems

• Iodonium salts allow for versatility and an efficient route to fluoro-iodobenzene, a precursor for Pd-mediated syntheses

• Current trends aim to develop more selective fluorinating reagents using Selectfluor-based methods and catalyst designs

18F Summary

30

Future Directions• Microfluidics

• Complete automation

31Lee, C. C., Science 2005, 310, 1793-1796., http://www.gehealthcare.com/euen/fun_img/products/radiopharmacy/products/fastlab-

index.html (accessed 2/5/2012).

Acknowledgements• Advisor:

Dr. Sandro Mecozzi

• Group Members:Elham NejatiAaron McCoyDr. Jun-Pil JeeWill TuckerKen SimmonsAndrew OskouiMatt Biller

• Special Thanks:Kat MyhreJoseph Moore

32

• Practice Talk Attendees:Patrick Robichaux Aaron

McCoyBen Haenni Allice

DangJon Jaworski Andrie

IosubChris Adams Anna Dunn